Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Eurofins Ntd Llc |
RCV000327267 | SCV000339046 | uncertain significance | not provided | 2016-01-19 | criteria provided, single submitter | clinical testing | |
| Counsyl | RCV000673223 | SCV000798401 | uncertain significance | Very long chain acyl-CoA dehydrogenase deficiency | 2018-03-08 | criteria provided, single submitter | clinical testing | |
| ARUP Laboratories, |
RCV000673223 | SCV000884960 | likely pathogenic | Very long chain acyl-CoA dehydrogenase deficiency | 2019-06-17 | criteria provided, single submitter | clinical testing | The ACADVL c.1328T>G; p.Met443Arg variant (rs886043236) is reported in the literature in an individual with VLCAD deficiency (Schiff 2013) who was also heterozygous for another variant classified as pathogenic in ClinVar (Variation ID: 203582); cultured fibroblasts from this individual showed no detectable VLCAD activity. Furthermore, functional analysis of p.Met443Arg expressed using an in vitro prokaryotic system yielded no activity, even though protein of the correct size was detected by western blot. Additionally, another variant at this codon (c.1328T>C; p.Met443Thr) has been reported in an individual with VLCAD deficiency (Li 2015). The p.Met443Arg variant is reported in ClinVar (Variation ID: 285852), but is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The methionine at codon 443 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be likely pathogenic. References: Li X et al. Very long-chain acyl-coenzyme A dehydrogenase deficiency in Chinese patients: eight case reports, including one case of prenatal diagnosis. Eur J Med Genet. 2015 Mar;58(3):134-9. Schiff M et al. Molecular and cellular pathology of very-long-chain acyl-CoA dehydrogenase deficiency. Mol Genet Metab. 2013 May;109(1):21-7. |
| Wong Mito Lab, |
RCV000673223 | SCV001365098 | uncertain significance | Very long chain acyl-CoA dehydrogenase deficiency | 2019-11-01 | criteria provided, single submitter | clinical testing | The NM_000018.3:c.1328T>G (NP_000009.1:p.Met443Arg) [GRCH38: NC_000017.11:g.7223871T>G] variant in ACADVL gene is interpretated to be Uncertain Significance based on ACMG guidelines (PMID: 25741868). This variant has been reported. This variant meets the following evidence codes reported in the ACMG guidelines: PP3 |
| Invitae | RCV000673223 | SCV001391136 | pathogenic | Very long chain acyl-CoA dehydrogenase deficiency | 2023-09-08 | criteria provided, single submitter | clinical testing | This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 443 of the ACADVL protein (p.Met443Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of ACADVL-related conditions (PMID: 23480858). ClinVar contains an entry for this variant (Variation ID: 285852). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ACADVL protein function. Experimental studies have shown that this missense change affects ACADVL function (PMID: 23480858). This variant disrupts the p.Met443 amino acid residue in ACADVL. Other variant(s) that disrupt this residue have been observed in individuals with ACADVL-related conditions (PMID: 25652019), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. |